rs80338684

Variant names:

• chr3-15635477-GCGGCTG-TCC
• rs80338684
• NM_001370658.1:c.38_44delGCGGCTGinsTCC

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PS1 PM2 PP5_Very_Strong

The NM_001370658.1(BTD):​c.38_44delGCGGCTGinsTCC​(p.Cys13PhefsTer36) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BTD NM_001370658.1 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18 O:1
• Conservation: PhyloP100: 1.63

Genes affected

BTD (HGNC:1122): (biotinidase) The protein encoded by this gene functions to recycle protein-bound biotin by cleaving biocytin (biotin-epsilon-lysine), a normal product of carboxylase degradation, resulting in regeneration of free biotin. The encoded protein has also been shown to have biotinyl transferase activity. Mutations in this gene are associated with biotinidase deficiency. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Pathogenic. Variant got 22 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 117 pathogenic variants in the truncated region.
• PS1: Transcript NM_001370658.1 (BTD) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-15635477-GCGGCTG-TCC is Pathogenic according to our data. Variant chr3-15635477-GCGGCTG-TCC is described in ClinVar as [Pathogenic]. Clinvar id is 1895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTD	NM_001370658.1	c.38_44delGCGGCTGinsTCC	p.Cys13PhefsTer36	frameshift_variant, missense_variant	Exon 2 of 4	ENST00000643237.3	NP_001357587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTD	ENST00000643237.3	c.38_44delGCGGCTGinsTCC	p.Cys13PhefsTer36	frameshift_variant, missense_variant	Exon 2 of 4		NM_001370658.1	ENSP00000495254.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Biotinidase deficiency Pathogenic:15 Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Nov 25, 2015

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Apr 24, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 15, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Cys13PhefsX36 (c.38_44delinsTCC) variant in BTD has been reported in >10 homozygous and > 10 compound heterozygous individuals with biotinidase deficiency and segregated with disease in 1 affected homozygous relative from 1 consanguineous family (Pomponio 1995 PMID: 7550325, Senanayake 2015 PMID: 28649532, Asgari 2016 PMID: 27845546, Wolf 2017 PMID: 27657684, Ferreira 2017 PMID: 28220409, Al-Eitan 2020 PMID: 31973013). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 1895) and has also been identified in as two separate variants (40_41delGG and c.44_45delGT) in gnomAD in 0.08% (4/4836) South Asian and 0.02% (15/68040) European chromosomes (http://gnomad.broadinstitute.org v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 13 and leads to a premature termination codon 36 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BTD gene is an established disease mechanism in autosomal recessive biotinidase deficiency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive biotinidase deficiency. ACMG/AMP Criteria applied: PVS1, PM3_Very Strong. -

Dec 20, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000060.2(BTD):c.98_104del7ins3(C33Ffs*36) is classified as pathogenic in the context of biotinidase deficiency. Sources cited for classification include the following: PMID 7550325. Classification of NM_000060.2(BTD):c.98_104del7ins3(C33Ffs*36) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -

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Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frameshift variant c.38_44delGCGGCTGinsTCC (p.Cys13PhefsTer36) in the BTD gene has been reported as homozygous/compound heterozygous state in individuals affected with biotinidase deficiency (Canda et al., 2018; Al-Eitan et al., 2020). Experimental studies have shown that this frameshift variation affects protein function (Mardhiah et al., 2019). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It is submitted to ClinVar as Pathogenic. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Oct 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BTD c.38_44delinsTCC; p.Cys13PhefsTer36 variant (rs80338684), also known as c.98_104delinsTCC; p.Cys33PhefsTer36 for NM_000060.2, is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with profound biotinidase deficiency (Al-Eitan 2020, Ferreira 2017, Pomponio 1995, Senanayake 2015) and is also reported in ClinVar (Variation ID: 1895). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting seven and inserting three nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Al-Eitan LN et al. Identification and Characterization of BTD Gene Mutations in Jordanian Children with Biotinidase Deficiency. J Pers Med. 2020 Jan 21;10(1):4. PMID: 31973013. Ferreira P, Chan A, Wolf B. Irreversibility of Symptoms with Biotin Therapy in an Adult with Profound Biotinidase Deficiency. JIMD Rep. 2017;36:117-120. PMID: 28220409. Pomponio RJ et al. Mutational hotspot in the human biotinidase gene causes profound biotinidase deficiency. Nat Genet. 1995 Sep;11(1):96-8. PMID: 7550325. Senanayake DN et al. First contiguous gene deletion causing biotinidase deficiency: The enzyme deficiency in three Sri Lankan children. Mol Genet Metab Rep. 2015 Feb 7;2:81-84. PMID: 28649532. -

Jun 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Cys33Phefs*36) in the BTD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BTD are known to be pathogenic (PMID: 20083419). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with biotinidase deficiency (PMID: 7550325, 27657684, 27845546, 28281033). This variant is also known as c.98-104del7ins3. ClinVar contains an entry for this variant (Variation ID: 373906). For these reasons, this variant has been classified as Pathogenic. -

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Molecular Genetics Lab, CHRU Brest

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1,PM3,PM2 -

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Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Suma Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Mar 31, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 14, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15776412, 22975760, 22011816, 31973013, 27845546, 26361991, 7550325, 28281033, 27657684, 28220409, 20083419, 28649532, 34302356, 33364171, 33083013, 32235217) -

Nov 03, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BTD c.98_104delinsTCC (p.Cys33Phefs*36) variant alters the translational reading frame of the BTD mRNA and causes the premature termination of BTD protein synthesis. This variant has been reported in the published literature in individuals with biotinidase deficiency (PMIDs: 9099842 (1997), 15776412 (2005), 20083419 (2010), 27845546 (2016), 27329734 (2016), 28220409 (2017), 27657684 (2017)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80338684; hg19: chr3-15676984;